Pancreatic cancer (PC) is the fourth leading cause of death from cancer in the US. Treatment options for this disease are extremely limited and prognosis is poor. At present, less than 6% of PC patients are alive after five years with an average survival time following diagnosis of 4-6 months, which is among the lowest for all cancers. It is clear that new therapies are urgently needed. Constitutively active KRAS is present in virtually all pancreatic tumors. Despite decades of work and numerous clinical trials, new therapies to inhibit the function of KRAS have been uniformly unsuccessful turning attention downstream for alternative points of intervention. Emerging data implicate TAK1 as a key downstream effector of KRAS function and reducing TAK1 expression or function both resulted in cytolysis of pancreatic tumor cell lines and potentiation of the effect of the chemotherapeutic gemcitabine. This establishes that TAK1 is a potential drug target for the treatment of PC. We are not aware of any TAK1 drug candidates in development. In this SBIR Phase I Confluence Life Sciences (CLS) proposes to develop a proprietary TAK1 inhibitor drug candidate for the treatment of PC. CLS has developed an innovative kinase drug discovery platform (KINect) that exploits our proprietary electrophilic kinase inhibitor library in the contet of structure-based drug design to rapidly identify and develop active, drug-like chemical cores into lead matter. The innovative nature of the KINect platform is unique in the industry and will significantly shorten the timeline for clinical candidate identification and increase the probabiliy of success. Using this approach CLS has recently identified a potent, proprietary TAK1 inhibitor lead compound, CDD-162. From this starting point, CLS proposes to develop TAK1 drug candidates focusing on the following specific aims: (1) using structure-based drug design, optimize current proprietary leads into 2-3 selective, bioavailable drug candidates that are effective inhibitors of TAK1, (2) determine the efficacy of TAK1 inhibitors in genotypically characterized human PC cell lines, and (3) determine TAK1 inhibitor efficacy in mouse models using human and mouse PC tumors. SBIR phase 2 studies will focus on product development. This proposal will advance the program through human Phase 1 clinical evaluation in PC patients. This clinical study will be coordinated by our collaborator, Dr David Linehan (Washington University Medical School). Supporting studies will include in vivo toxicology, PK and additional in vivo cancer efficacy models. The drug candidate product will be of great interest to cancer drug companies and we anticipate a co- development partnership license. Commercial deals for assets at this stage are highly precedent in the industry and typically total >$100M. Given the great need for an effective therapeutic for PC we believe that the development of a safe TAK1 inhibitor drug candidate will have a major medical impact.